Atriopeptins are polypeptides isolated from mammalian atria that display diuretic and natriuretic activity. These atrial polypeptides have been purified and sequenced [see, e.g., U.S. Pat. No. 4,496,544 issued to P. Needleman; M. G. Currie et al., "Purification And Sequence Analysis Of Bioactive Atrial Peptides (Atriopeptins)", Science, 223, pp. 67-69 (1984); T. G. Flynn et al., "The Amino Acid Sequence Of An Atrial Peptide With Potent Diuretic And Natriuretic Properties", Biochem. Biophys. Res. Comm., 117 (No. 3), pp. 859-65 (1983)]. These peptides have also been referred to in the art as cardionatrin [see, e.g., A. J. deBold et al., "Cardionatrin I - A Novel Heart Peptide With Potent Diuretic And Natriuretic Properties", Life Sci., 33, pp. 297-302 (1983)] and atrial natriuretic factors or peptides [see, e.g., N. G. Seidah et al., "Amino Acid Sequence Of Homologous Rat Atrial Peptides", Proc. Natl. Acad. Sci. USA, 81, pp. 2640-44 (1984) and K. Kangawa et al., "Purification And Complete Amino Acid Sequence Of Beta-Rat Atrial Natriuretic Polypeptide (.beta.-rANP) Of 5,000 Daltons", Biochem. Biophys. Res. Comm., 119 (No. 3), pp. 933-40 (1984)].
While all atriopeptins appear to possess diuretic and natriuretic activity, the atriopeptins have been further characterized as comprising several subtypes that display different muscle relaxant activities. Atriopeptin 21 (also referred to in the art as atriopeptin I) is a 21-amino acid polypeptide that relaxes only intestinal smooth muscle in vitro. Atriopeptins 23 and 24 (also known in the art as atriopeptins II and III, respectively) have the same amino acid sequence as atriopeptin 21 except for an additional Phe-Arg or Phe-Arg-Tyr, respectively, at the carboxy terminal end of the peptide. These atriopeptins relax both intestinal and vascular smooth muscles in vitro [see, e.g., M. G. Currie et al., supra; R. J. Winquist et al., "Atrial Natriuretic Factor Elicits An Endothelium Independent Relaxation And Activates Particulate Guanylate Cyclase In Vascular Smooth Muscle", Proc. Natl. Acad. Sci., 81, pp. 7661-64 (1984)]. Furthermore, atriopeptins 23 and 24 have been shown to selectively increase renal blood flow and decrease renal vascular resistance [see, e.g., T. Oshima et al., "An Atrial Peptide Is a Potent Renal Vasodilator Substance", Circ. Res., 54, pp. 612-16 (1984)].
Thus, it is known that atriopeptins 23 and 24 are potent selective renal vasodilators that affect the renal vascular bed in a dosage-dependent fashion. Although the catecholamine, dopamine, is also known to possess renal vasodilator effects, dopamine reduces the resistance in other vascular beds as well and therefore does not display the unique renal specificity exhibited by the atriopeptins. [See, e.g., T. H. Hintze et al., "Atriopeptins: Renal-Specific Vasodilators In Conscious Dogs", Am. J. Physiol., 248, pp. H587-91 (1985)]. Studies to date, however, have indicated that the renal vasodilator activity of atriopeptins 23 and 24 is transient [see T. H. Hintze et al., supra].
It is known that norepinephrine, epinephrine and other sympathomimetic amines or catecholamines act at various target sites within the body to mediate the wide range of central and peripheral functions of the sympathetic nervous system. Those sites are characterized by the presence of one or both of two distinct receptors specific for catecholamines. These receptors have been designated the .alpha.- and .beta.-adrenergic receptors and have been further characterized into subclasses. For example, .beta..sub.1 -adrenergic receptors are found primarily in cardiac tissue, .beta..sub.2 -adrenergic receptors are found in smooth muscle tissue and gland cells, .alpha..sub.1 -adrenergic receptors are found primarily at postsynaptic effector sites in smooth muscle tissue and gland cells and .alpha..sub.2 receptors are found on nerve terminals. Thus, the catecholamines exert their homeostatic regulatory activity via an initial binding to these receptors on the surface of the cells of the particular tissue to be regulated. Furthermore, it is well established that the catecholamines exert different, often contrasting effects, on the tissues of the body depending upon whether they bind to an .alpha.- or .beta.-receptor. For a general review of the sympathetic nervous system, in particular, the biology and mechanisms of action of the catecholamines, see A. G. Gilman et al. (eds.), The Pharmacological Basis Of Therapeutics, Chapter 8, pp. 138-75, MacMillan Publishing Co., Inc., New York (6th ed. 1980).
It is also known that certain chemical compounds interfere with the ability of the catecholamines to bind to their target .alpha.- or .beta.-receptors. These compounds have been termed adrenergic receptor blocking agents, more specifically, .alpha.- or .beta.-adrenergic antagonists. These agents act by binding selectively to either the .alpha. or .beta. class of adrenergic receptor, thus preventing the catecholamine from binding to the receptor and exerting its effect.
The .alpha.- and .beta.-adrenergic blocking agents are two distinct classes of compounds with different biological effects and uses. This is so because they are compounds that interact with different receptor molecules on different tissues and interfere with different catecholamine effects. For example, since the effect of catecholamine interaction with .alpha..sub.1 -receptors in smooth muscle is generally excitatory, an .alpha..sub.1 -adrenergic blocking agent, such as prazosin, causes a relaxation or dilation of the muscle tissue. In contrast, since the effect of catecholamine action on .beta..sub.2 -receptors in smooth muscle is inhibitory, .beta..sub.2 -adrenergic blocking agents generally cause a constriction of that tissue. Furthermore, because the effects of the catecholamines vary depending upon the tissue on which they are acting, the amounts and types of receptors in that tissue and the particular catecholamine in question, the action and use of any particular adrenergic blocking agent will depend upon these factors as well. For a general review of these blocking agents and their varying effects, see A. G. Gilman et al. (eds.), The Pharmacological Basis Of Therapeutics, supra, pp. 176-210.
Alternatively, ganglionic blocking agents act at the autonomic ganglia of the sympathetic nervous system and cause a decrease in the release of the catecholamine, norepinephrine, thereby eliminating stimulation of .alpha. receptors in the various tissues of the body. In this way, these agents indirectly block the interaction of norepinephrine with .alpha. receptors.
The general use of .beta.-adrenergic blocking agents in the treatment of hypertension and cardiovascular disease is known. For example, the use of a .beta.-adrenergic blocking agent in combination with a vasodilator and a diuretic for the treatment of arterial hypertension was referred to in German patent application No. 2230010. Similarly, U.S. Pat. No. 4,529,604, issued to C. Kaiser, refers to the use of the well known .beta.-blocking agent, propranolol, in combination with dopamine derivatives, to potentiate the vasodilator effect of the dopamine compounds for the treatment of hypertension. Compounds possessing both .beta.-adrenergic blocking and vasodilator activities for the treatment of hypertension were referred to in U.S. Pat. Nos. 4,053,605, 4,092,419 and 4,139,535, issued to J. J. Baldwin, U.S. Pat. No. 4,495,352, issued to W. E. Kreighbaum, and Japanese patent application No. 0044678 and and 0225069. And, European patent application 106,335.7 refers to pharmaceutical compositions which may include a .beta.-adrenergic blocking agent together with a coronary vasodilator for the treatment of coronary heart disease.
The potential of .alpha.-adrenergic and ganglionic blocking agents for therapeutic uses is less established. This is due to the possibility of several side effects of treatment at high dosage such as postural hypotension [see, e.g., U.S. Pat. No. 4,001,238, issued to R. A. Partyka and A. G. Gilman et al. (eds.), The Pharmacological Basis Of Thereaputics, supra, pp. 186-88 and 211-19].